This invention relates to a process for preparing crystalline loracarbef monohydrate by drying loracarbef isopropanolate to provide loracarbef anhydrate and then hydrating the loracarbef anhydrate to provide loracarbef monohydrate.
The .beta.-lactam antibiotic of the formula (I) ##STR2## is a potent, orally active antibiotic known as loracarbef. The antibiotic is described, for example, in Hashimoto et al., U.S. Pat. Ser. No. 4,335,211.
Loracarbef has been isolated in various forms, including the crystalline monohydrate form, which is disclosed in European Patent Publication (EPA) 0,311,366. Other known solvate forms of the compound are disclosed in Eckrich et al., U.S. Ser. No. 4,977,257. The crystalline dihydrate form of loracarbef is disclosed in EPA 0,369,686.
As indicated in EPA 0,369,686, the crystalline monohydrate form of loracarbef may be prepared by first suspending loracarbef dihydrate in water and then effecting solution by the addition of acid followed by the adjustment of the pH with base, or by the addition of base followed by acid. The resultant loracarbef may be crystallized and then isolated by filtration. Hereinafter, this process will be referred to as "the filtration process."
Crystalline loracarbef monohydrate is a fine, "hair-like" crystal which results in a very slow filtration. The monohydrate crystals tend to form a mat on the filter which prevents or reduces the ability to complete filtration and which requires the crystals to be washed with water. Since loracarbef monohydrate is moderately soluble in water, (approximately 10 mg/ml), this washing decreases the yield.
The filtration process is considered a commercially unattractive process for preparing loracarbef monohydrate in light of the difficulties with the filtration step. Subsequently, it was discovered that crystalline loracarbef monohydrate could be produced more efficiently by exposing a crystalline isopropanolate form of loracarbef to a temperature of from about 50.degree. C. to about 90.degree. C. and a relative humidity of from about 60% to about 100%. Hereinafter, this process will be referred to as "the isopropanolate process." Since this process is a solid state conversion of loracarbef isopropanolate to loracarbef monohydrate, it could be effected without filtering the crystalline monohydrate, thus providing a more efficient process.
However, the isopropanolate process is also considered commercially unattractive because it yields loracarbef monohydrate in the form of a fine, fluffy powder with a density of approximately 0.2 g/ml. This density renders the bulk product, loracarbef monohydrate, very difficult to formulate. Since this compound is intended for pharmaceutical use, the ability to formulate the bulk product is critical. For loracarbef monohydrate, a density of greater than or equal to 0.5 g/ml is desired in order to facilitate the formulation of the bulk product. Thus, it was necessary to modify the isopropanolate process in order to obtain a bulk product with a sufficient density such that the product could be formulated for pharmaceutical use.
Another disadvantage of the isopropanolate process is that the resultant loracarbef monohydrate can contain up to 5% residual isopropanol (by weight). Since it is generally accepted that solvent content should be kept at a minimum in products intended for human use, most of this residual isopropanol must be removed from the final product. Typically, it is desirable to decrease the level of isopropanol to less than 1.0% (by weight).
The residual isopropanol may be removed from the loracarbef monohydrate by drying the crystals under reduced pressure of about 0 mm Hg to about 400 mmHg at a temperature of from about 25.degree. C. to about 80.degree. C. A consequence of the drying procedure is that some of the water in the loracarbef monohydrate crystal may also be removed. Thus, if the mixture is dried too much, it will affect the chemical makeup of the loracarbef monohydrate by reducing the water content although X-ray analysis indicates that the crystalline structure remains the same.
The removal of too much water during the drying process creates an additional problem since loracarbef monohydrate having less than approximately 5% water (by weight) will absorb water from the air during storage and further processing. If this rehydration occurs, the potency of the material will change such that an accurate dosage during the formulation process will not be obtained.
Accordingly, the present invention provides a facile conversion of loracarbef isopropanolate to loracarbef monohydrate that results in a commercially desirable form of the bulk product.